Fetal Fibronectin

Abstract & Commentary

For good reason, much recent attention has been directed toward diminishing preterm birth, a problem that continues to be the major cause of infant mortality. Although little headway has been made in the treatment of preterm labor (PTL), substantial progress has been gained in the diagnostic component of PTL investigation. Two of the most studied predictors of PTL, feto-fibronectin (fFN) and cervical length (CL) have been applied mostly to populations at high risk for PTL. However, recently an article appeared by Iams and colleagues that assessed these diagnostic modalities in a low-risk population.

Data from a subset of 2197 patients enrolled in the now famous Preterm Prediction Study who were either primigravida or had no risk factors for PTL were analyzed. Bishop curves, cervical length by transvaginal ultrasound, and cervical fetal fibronectin were obtained in all of the above patients at 24 weeks’ gestation.

Three percent of these low-risk patients delivered spontaneously before 35 weeks, a prevalence rate not unexpected in this low-risk setting. All 3 factors were significantly associated with preterm birth (Bishop score of > 4, relative risk [RR] = 3.6, fFN of > 50 ng/mL, RR = 8.2; cervix of < 2.5 cm, RR = 6.9). However, the sensitivities were low for each of the tests (high Bishop score, 23.4%, positive fFN 23.4%, and short cervix 39.1%). From this study one could conclude that, because of the low sensitivities, a screening program using these diagnostic tests in a population with a low prevalence rate would not be efficacious.

The article was chosen as a springboard for discussion not because of its less than exciting outcomes. It was chosen to simply point out that this study’s results should not be extrapolated to a high-risk population where the diagnostic potential of fFN and, in some cases, CL, continues to burn brightly. (Iams JD, et al. Am J Obstet Gynecol. 2001;184:652-655.)

Comment by John C. Hobbins, MD

Fetal fibronectin is a glycoprotein in the interface between the chorion and decidua, which finds its way into the cervix and vagina when this interface is unstable. Normally it is found in the cervix until about 20 weeks, after which time the cervix is virtually fibronectin-free until just before labor ensues. For this reason, it has been studied as a predictor of PTL and, recently, as a predictor of successful labor induction.

Most studies have concentrated on the ability of a sample taken from the cervix and vagina at 24 weeks to predict preterm birth (PTB) prior to 35 weeks with the idea that prevention (intervention) be initiated for those at highest risk of PTB. A majority of the studies with large enough numbers to answer this question have been spawned from a large collaborative study sponsored by the National Institutes of Child Health & Human Development (NICHD) involving many centers in the NICHD Network (Preterm Prediction Study).

Another investigative focus with extremely important clinical connotations is the ability of fFN to predict PTB in third trimester patients presenting with preterm contractions. Investigation in this area is composed mostly of studies with relatively small numbers of patients. Both investigative questions have huge public health implications. PTB is perhaps one of the most vexing problems in obstetrics, and if clinicians knew which patients were at highest risk of PTB by the end of the second trimester through yet-to-be-determined preemptive therapeutic strikes, PTB might be averted.

The second question is just as important to answer and, perhaps, has a more reasonable chance of immediate success. Only a small percentage of patients with preterm contractions are truly in PTL, so we have been treating everyone with preterm contractions with tocolytics, antibiotics, etc to potentially affect only the few who really might benefit from this therapy. This shotgun approach is fraught with unnecessary confinement and/or uncomfortable side effects for the majority of patients, and prodigious costs have been generated through unnecessary hospitalizations and medications. Even studies showing negative results with various interventions in patients with preterm contractions have been flawed by an inability to tell who really is in PTL, thereby diluting the difference in results between treatment and controls.

Fetal fibronectin has been on the scene since the early 1990s. However, the assay only recently has been available in hospitals around the country. Prior to this time, the only way results could be obtained was to send the cervical/vaginal specimen to 1 central lab in the United States. By the time the result is returned 1 or 2 days later, the patient had already declared herself, and if the result was "negative," many caregivers were reluctant to believe the results and to stop the therapy.

Now the results are available within hours, allowing clinicians to concentrate potential therapy on those who really need it. However, the true worth of the test is in its negative predictive value, and those not confident in the data in the literature regarding the test’s ability to exclude true PTL need not order the test.

Here is the current story on fFN in symptomatic third trimester patients. Perhaps the most instructive study involved 763 patients admitted with symptoms of PTL and cervical dilation of less than 3 cm and intact membranes. If fFN was positive (in 150 patients), 20 (13%) delivered within 7 days, 25 (16.7%) delivered within 14 days, and 67 (44.7%) delivered before 37 weeks. Most important, if the fFN was negative (613 patients), only 3 delivered within 7 days, 5 delivered within 2 weeks, and 95 delivered before 37 weeks. This results in negative- predictive values of 99.5%, 99.2%, and 84.5%, respectively. This simply meant that for patients admitted with the presumed diagnosis of PTL, if their fFN was negative, only 1 in 200 would deliver within 2 weeks of admission.

Using this information clinically to decide which patients with preterm contractions to treat with tocolytics and which patients to transfer to a tertiary care center, Joffe in a "before-and-after" type study showed a significant decrease in admissions for PTL, length of stays for those admitted, and decreased use of tocolytics after fFN was introduced as a diagnostic test. In a recent Australian study, Giles et al showed a negative fFN result reduced maternal transport for PTL to a tertiary care hospital by 90% and diminished the need for tocolytics by 64%. They calculated that the cost savings for 58 fFN-negative patients not transferred by fixed wing was $30,000. The cost savings from avoidance of hospitalization were even more startling. So—using fFN wisely can allow clinicians to concentrate on those patients who truly require tocolytic attention. Also, contemporary studies should now be able to better demonstrate the efficacy of various tocolytic methods by excluding most of the patients who are not at risk for PTB.

Let us now turn back to fFN as a second trimester predictor of PTL. The largest and most comprehensive study thus far is the large Preterm Prediction Study, from which the low-risk data cited above were extracted. The fFN bottom line in this study is that any patient with a positive fFN at 22-24 weeks has a 14 times greater chance of delivering a baby at less than 32 weeks (a threshold with the greatest neonatal implications). This and other studies have also suggested that a second trimester positive fFN predisposed patients to a higher risk of having bacterial vaginosis, premature rupture of membranes, and having a short cervix (< 2.5 cm).

A short cervix alone at 22-24 weeks is also a reasonable predictor of PTB or asymptomatic PTL, but like fFN, a single number, above which one can be reassured and below which one should be worried, has been difficult to come by. In the now frequently cited earlier Iams study, a 2.5 cm cervical length by transvaginal sonography seemed to be the best screening end point. However, if a threshold of 1.5 cm was chosen, as published by a British group, the RR of PTB earlier than 33 weeks was 46.2, compared with 8.1 for fFN.

As shown by Goldenberg and colleagues, fFN, cervical length, and a history of PTB have an exponential effect on risk of PTB. For example, if a patient at 24 weeks has neither a positive history, a short cervix (< 2.5 cm), nor a positive fFN, she runs a 0.5% chance of delivering preterm (< 35 weeks). Any 2 of the above risk factors gives a patient a 35-fold increase in likelihood of a PTB, and 3 of 3 factors increases the risk by 100-fold.

Lastly, perhaps even the level of fFN can be fine tuned to better suit the clinical situation. In one study, it was shown through receiver-operating characteristic (ROC) analysis that the original fFN cutoff point of 50 ng/mL was reasonable in a population of mixed risk. However, perhaps this threshold should be adjusted upward or downward depending upon the degree of risk for each patient. The same could also be said for cervical length. Only a few studies have addressed the adjunctive usefulness of the 2 tests, but we will have to wait for these answers to evolve in expanded high-risk studies. In the meantime, it looks like fFN can play an extremely important role in the early prediction of PTL and in those patients presenting in the third trimester with preterm contractions. Enlightened use of this diagnostic test should decrease costs, minimize side effects, and allay patient and caregiver angst.

Suggested Reading

1. Goldenberg RL, et al. Am J Obstet Gynecol. 1997;177:8-12.

2. Peaceman AM, et al. Am J Obstet Gynecol. 1997;17:
13-18.

3. Joffe GM, et al. Am J Obstet Gynecol. 1999;180:
581-586.

4. Giles W, et al. Am J Obstet Gynecol. 2000;182:439-442.

5. Iams JD, et al. N Engl J Med. 1996;334:567-572.

6. Heath VC, et al. Br J Obstet Gynaecol. 2000;107:
1276-1281.

7. Goldenberg RL, et al. Am J Public Health. 1998;88:
233-238.

8. Goepfert AR, et al. Am J Obstet Gynecol. 2000;183:
1480-1483.